Seminars in Pediatric Neurology
Volume 13, Issue 3 , Pages 142-148 , September 2006

Brain Iron Metabolism

  • Tracey A. Rouault, MD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Tracey A. Rouault, MD, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, 900 Rockville Pike, Bethesda, MD 20892.
    • ,
  • Sharon Cooperman, MD, PhD

References 

  1. Andrews NC. Metal transporters and disease. Curr Opin Chem Biol. 2002;6:181–186
  2. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488
  3. Fleming MD, Trenor CC, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383–386
  4. McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291:1755–1759
  5. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781
  6. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000;5:299–309
  7. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906–19912
  8. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999;21:195–199
  9. Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789–801
  10. Quigley JG, Yang Z, Worthington MT, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell. 2004;118:757–766
  11. Latunde-Dada GO, Simpson RJ, McKie AT. Recent advances in mammalian haem transport. Trends Biochem Sci. 2006;31:182–188
  12. Rouault TA. The intestinal heme transporter revealed. Cell. 2005;122:649–651
  13. Aisen P. Transferrin, the transferrin receptor, and the uptake of iron by cells. Met Ions Biol Syst. 1998;35:585–631
  14. Aisen P. Transferrin receptor 1. Int J Biochem Cell Biol. 2004;36:2137–2143
  15. Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264–1269
  16. Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005;105:1867–1874
  17. Pantopoulos K. Iron metabolism and the IRE/IRP regulatory system: An update. Ann N Y Acad Sci. 2004;1012:1–13
  18. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: Molecular control of mammalian iron metabolism. Cell. 2004;117:285–297
  19. Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2:406–414
  20. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191–200
  21. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–2093
  22. Ganz T, Nemeth E. Iron imports.IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199–G203
  23. Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem. 1999;274:20826–20832
  24. Fleming RE, Britton RS. Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2006;290:G590–G594
  25. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77–82
  26. Babitt JL, Huang FM, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–539
  27. Beutler E. Hemochromatosis: Genetics and pathophysiology. Annu Rev Med. 2006;57:331–347
  28. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399–409
  29. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53
  30. Lai CH, Kuo KH. The critical component to establish in vitro BBB model: Pericyte. Brain Res Brain Res Rev. 2005;50:258–265
  31. Hellstrom M, Gerhardt H, Kalen M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 2001;153:543–553
  32. Bradbury MW. Transport of iron in the blood-brain-cerebrospinal fluid system. J Neurochem. 1997;69:443–454
  33. Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol. 2000;20:77–95
  34. Enerson BE, Drewes LR. The rat blood-brain barrier transcriptome. J Cereb Blood Flow Metab. 2005;26:959–973
  35. Burdo JR, Antonetti DA, Wolpert EB, et al. Mechanisms and regulation of transferrin and iron transport in a model blood-brain barrier system. Neuroscience. 2003;121:883–890
  36. Beard JL, Wiesinger JA, Li N, et al. Brain iron uptake in hypotransferrinemic mice: Influence of systemic iron status. J Neurosci Res. 2005;79:254–261
  37. Burdo JR, Menzies SL, Simpson IA, et al. Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res. 2001;66:1198–1207
  38. Moos T, Morgan EH. The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J Neurochem. 2004;88:233–245
  39. Wu LJ, Leenders AG, Cooperman S, et al. Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res. 2004;1001:108–117
  40. Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem. 2003;278:27144–27148
  41. Oide T, Yoshida K, Kaneko K, et al. Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia. Neuropathol Appl Neurobiol. 2006;32:170–176
  42. Brightman MW, Kaya M. Permeable endothelium and the interstitial space of brain. Cell Mol Neurobiol. 2000;20:111–130
  43. Takeda A, Devenyi A, Connor JR. Evidence for non-transferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice. J Neurosci Res. 1998;51:454–462
  44. Erikson KM, Aschner M. Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter. Neurotoxicology. 2006;27:125–130
  45. Abbott NJ. Dynamics of CNS barriers: Evolution, differentiation, and modulation. Cell Mol Neurobiol. 2005;25:5–23
  46. Connor JR, Menzies SL. Cellular management of iron in the brain. J Neurol Sci. 1995;134(Suppl):33–44
  47. Moos T. Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. J Comp Neurol. 1996;375:675–692
  48. Hoepken HH, Korten T, Robinson SR, et al. Iron accumulation, iron-mediated toxicity and altered levels of ferritin and transferrin receptor in cultured astrocytes during incubation with ferric ammonium citrate. J Neurochem. 2004;88:1194–1202
  49. Dickinson TK, Connor JR. Immunohistochemical analysis of transferrin receptor: Regional and cellular distribution in the hypotransferrinemic (hpx) mouse brain. Brain Res. 1998;801:171–181
  50. Kaur C, Ling EA. Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia. Neurosci Lett. 1999;262:183–186
  51. Hahn P, Qian Y, Dentchev T, et al. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci U S A. 2004;101:13850–13855
  52. Rodriguez Martinez A, Niemela O, Parkkila S. Hepatic and extrahepatic expression of the new iron regulatory protein hemojuvelin. Haematologica. 2004;89:1441–1445
  53. Golub MS, Germann SL, Araiza RS, et al. Movement disorders in the Hfe knockout mouse. Nutr Neurosci. 2005;8:239–244
  54. Dekker MC, Giesbergen PC, Njajou OT, et al. Mutations in the hemochromatosis gene (HFE), Parkinson’s disease and parkinsonism. Neurosci Lett. 2003;348:117–119
  55. Costello DJ, Walsh SL, Harrington HJ, et al. Concurrent hereditary haemochromatosis and idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75:631–633
  56. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–7810
  57. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037–1044
  58. Cardarelli G, Anatra GM. Hepcidin: A key peptide in iron metabolism. Minerva Med. 2003;94:135–139
  59. Moos T, Morgan EH. Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. J Neurosci Res. 1998;54:486–494
  60. Bennett MV, Contreras JE, Bukauskas FF, et al. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 2003;26:610–617
  61. Sloot WN, Gramsbergen JB. Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res. 1994;657:124–132
  62. Tjalve H, Henriksson J. Uptake of metals in the brain via olfactory pathways. Neurotoxicology. 1999;20:181–195
  63. Rao DB, Wong BA, McManus BE, et al. Inhaled iron, unlike manganese, is not transported to the rat brain via the olfactory pathway. Toxicol Appl Pharmacol. 2003;193:116–126
  64. Hahn P, Dentchev T, Qian Y, et al. Immunolocalization and regulation of iron handling proteins ferritin and ferroportin in the retina. Mol Vis. 2004;10:598–607
  65. Dentchev T, Hahn P, Dunaief JL. Strong labeling for iron and the iron-handling proteins ferritin and ferroportin in the photoreceptor layer in age-related macular degeneration. Arch Ophthalmol. 2005;123:1745–1746
  66. Zhang P, Land W, Lee S, et al. Electron tomography of degenerating neurons in mice with abnormal regulation of iron metabolism. J Struct Biol. 2005;150:144–153
  67. Mackenzie B, Ujwal ML, Change MH, Romero MF, Hediger MA. Divalent metal-ion transporter DMT1 mediates both H+-coupled Fe2+ transport and uncoupled fluxes. Pflugers Arch. 2006;451:544–558
  68. Dwork AJ, Lawler G, Zybert PA, et al. An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Res. 1990;518:31–39
  69. Dwork AJ. Effects of diet and development upon the uptake and distribution of cerebral iron. J Neurol Sci. 1995;134(Suppl):45–51
  70. Malecki EA, Cook BM, Devenyi AG, et al. Transferrin is required for normal distribution of 59Fe and 54Mn in mouse brain. J Neurol Sci. 1999;170:112–118
  71. de Arriba Zerpa GA, Saleh MC, Fernandez PM, et al. Alternative splicing prevents transferrin secretion during differentiation of a human oligodendrocyte cell line. J Neurosci Res. 2000;61:388–395
  72. Bartzokis G, Tishler TA, Shin IS, et al. Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann N Y Acad Sci. 2004;1012:224–236
  73. Zecca L, Youdim MB, Riederer P, et al. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5:863–873
  74. Beard JL, Felt B, Schallert T, et al. Moderate iron deficiency in infancy: Biology and behavior in young rats. Behav Brain Res. 2006;170:224–232
  75. Xu X, Pin S, Gathinji M, et al. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci. 2004;1012:299–305
  76. Gregory A, Hayflick SJ. Neurodegeneration with brain iron accumulation. Folia Neuropathol. 2005;43:286–296
  77. Curtis AR, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet. 2001;28:350–354
  78. LaVaute T, Smith S, Cooperman S, et al. Targeted deletion of iron regulatory protein 2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27:209–214
  79. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, et al. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood. 2005;106:1084–1091
  80. Galy B, Ferring D, Minana B, et al. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood. 2005;106:2580–2589
  81. Frantom PA, Seravalli J, Ragsdale SW, et al. Reduction and oxidation of the active site iron in tyrosine hydroxylase: Kinetics and specificity. Biochemistry. 2006;45:2372–2379
  82. Perry TL, Norman MG, Yong VW, et al. Hallervorden-Spatz disease: Cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus. Ann Neurol. 1985;18:482–489
  83. Beard JL, Erikson KM, Jones BC. Neurobehavioral analysis of developmental iron deficiency in rats. Behav Brain Res. 2002;134:517–524
  84. Levenson CW, Cutler RG, Ladenheim B, et al. Role of dietary iron restriction in a mouse model of Parkinson’s disease. Exp Neurol. 2004;190:506–514
  85. Leapman RD. Detecting single atoms of calcium and iron in biological structures by electron energy-loss spectrum-imaging. J Microsc. 2003;210:5–15
  86. Francis K, Van Beek J, Canova C, et al. Innate immunity and brain inflammation: the key role of complement. Expert Rev Mol Med. 2003;2003:1–19

 Supported by the intramural program of the National Institute of Child Health and Human Development.

PII: S1071-9091(06)00101-X

doi: 10.1016/j.spen.2006.08.002

Seminars in Pediatric Neurology
Volume 13, Issue 3 , Pages 142-148 , September 2006

Article Tools

* Image Usage & Resolution